Clinical Trials

This is the first evaluation of edoxaban in pediatric subjects. In this Phase 1 study, a
single dose of edoxaban will be given to pediatric subjects who require anticoagulant
therapy to see what the body does to the drug (pharmacokinetics) and what the drug does to
the body (pharmacodynamics), and to compare if these effects are similar to those observed
in adults.

Abstract

Central venous access devices (CVADs) are used in the care of paediatric haemophilic patients with difficult peripheral access, but their use is limited by complications such as infection. We previously published our experience with monthly recombinant tissue plasminogen activator (r-tPA) administration to CVADs of haemophilic patients as an intervention for infection prophylaxis, which suggested a 10-fold decrease in infection rate compared to published rates without r-tPA.This study was conducted to assess the CVAD infection rate in an expanded haemophilia cohort receiving r-tPA over an extended period.A retrospective review was performed on patients with haemophilia who received monthly r-tPA to CVADs, with data collected from January 1, 2008 to December 31, 2012. The data were merged with the previously reported data set (collected from June 1, 1998 to December 31, 2007).Over the entire observation period, there were 46 350 CVAD days among 32 patients [26 severe factor VIII (FVIII) deficiency, six severe FIX deficiency]. Eight patients received immune tolerance therapy for inhibitors and 24 patients received prophylactic factor administration. No patients were HIV positive. Three infections were observed, with an overall infection rate of 0.06 infections per 1000 CVAD days.A low CVAD infection rate, similar to that observed in our previous study (0.04 per 1000 CVAD days), was observed in this expanded haemophilia cohort treated with prophylactic r-tPA, supporting the use of monthly r-tPA as CVAD infection prophylaxis in haemophilia patients.

Abstract

To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey.International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course.A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide.The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Abstract

To evaluate the practice of empiric antibiotics for febrile, nonneutropenic pediatric oncology patients with a central venous catheter (CVC) in place.Episodes of fever without neutropenia (absolute neutrophil count [ANC] ≥500 cells/mm(3)) were reviewed retrospectively in pediatric oncology patients with a CVC undergoing chemotherapy. Characteristics and symptoms were compared between patients with bacteremia and patients without bacteremia.A total of 392 episodes of nonneutropenic fever in 138 subjects (52 females; 38%) were reviewed. In this cohort, the median age at an episode was 7 years, and the majority of patients had a diagnosis of acute leukemia (54%). Median ANC was 3100 cells/mm(3) (IQR, 1570-5980 cells/mm(3)). Median temperature was 38.7°C (IQR, 38.3-39.2°C). Twenty-four infectious episodes (6%) occurred in 18 subjects, and 5 CVCs required removal; all patients requiring removal admitted and received antibiotics owing to chills. There were no significant difference in age, sex, or ANC between patients with bacteremia and those without bacteremia; however, mean temperature was higher in the patients with bacteremia (39.4°C vs 38.7°C; P = .003). No deaths due to sepsis occurred, and no CVCs were removed because antibiotics were not administered empirically.Our practice of observing pediatric oncology patients undergoing chemotherapy with CVCs who are not neutropenic does not appear to lead to increased serious adverse outcomes and avoids antibiotic exposure for >90% of patients without a bacterial infection.

Abstract

Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.

Abstract

We describe a child initially diagnosed with multi-focal infantile hemangioma (cutaneous, hepatic, pulmonary), a benign vascular lesion, which underwent malignant transformation to angiosarcoma. The use of anti-angiogenic agents, such as bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, has been reported in adults with angiosarcoma. Treatment with chemotherapy (gemcitabine and docetaxel) and bevacizumab resulted in disease response with progression free survival of 12 months. This report describes the response to chemotherapy and bevacizumab in a child with angiosarcoma and highlights the potential for malignant transformation of benign vascular lesions and the need for careful monitoring.

Abstract

A 16-month-old previously healthy boy was admitted to the hospital with respiratory distress and thrombocytopenia. Initial workup demonstrated large pleural and pericardial effusions. The patient had no cutaneous abnormality on physical examination, and his initial chest CT (computed tomography) was nondiagnostic. He required multiple platelet transfusions, chest tube placement, and pericardiocentesis. Sixteen days after admission, a chest MRI (magnetic resonance imaging) revealed a large infiltrative mass of the superior mediastinum, consistent with kaposiform hemangioendothelioma (KHE). The patient's thrombocytopenia was due to associated Kasabach-Merritt phenomenon (KMP). The patient now has complete resolution of KMP after medical treatment with prednisolone, aminocaproic acid, vincristine, and aspirin.

Abstract

A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization.A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive.Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response.Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA.

Abstract

Immune thrombocytopenia (ITP) in children less than one year of age is less well characterized compared to ITP in toddlers and school-age children. We performed a 10-year retrospective review of ITP patients in this age-cohort at our institution. Diagnosis and classification were made according to the 2009 International Working Group criteria. Fourteen infants were identified. Their bleeding scores were Grades 1 to 2 (79%), Grade 3 (22%), Grades 4 to 5 (0%). Eight patients received treatment with a 75% response rate. Three patients (21%) developed chronic ITP. These observations suggest that ITP in very young patients is similar to typical childhood ITP.

Abstract

Pediatric patients with refractory multisystem Langerhans cell histiocytosis (LCH) have a poor prognosis despite aggressive chemotherapy. Salvage therapy with cytarabine and cladribine has shown promise as an effective treatment but is associated with significant toxicity. A previous report described two patients with refractory LCH who had a rapid response to single-agent clofarabine with minimal toxicity. In this report, we describe four children with refractory, risk-organ-positive LCH who were treated with clofarabine and provide follow-up for the two previously reported cases. The results support development of a formal trial evaluating clofarabine as front-line salvage for refractory LCH.

Abstract

We explored potential risk factors associated with Langerhans cell histiocytosis (LCH) in a predominantly Hispanic population in Los Angeles. Sixty children with LCH (cases) and, 150 randomly selected patients (controls) were interviewed. There was no statistically significant difference between cases and controls in the following: Family history of thyroid disease, smokers in the family, maternal problems during pregnancy, and pesticide exposure. Cases were more likely to report a family history of cancer (OR 2.5), infection during infancy (OR 2.76), and parental occupational exposure to metal, granites, or wood dust (OR 2.48).

Abstract

Treatment choice in pediatric immune thrombocytopenia (ITP) is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies.The objective of this study was to evaluate univariate and multivariable predictors of platelet count response to rituximab. After local IRB approval, 565 patients with chronic ITP enrolled and met criteria for this study in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and October 2010. Treatment response was defined as a post-treatment platelet count ? 50,000/µl within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively.Eighty (14.2%) patients were treated with rituximab with an overall response rate of 63.8% (51/80). Univariate correlates of response to rituximab included the presence of secondary ITP and a positive response to steroids. In multivariable analysis, response to steroids remained a strong correlate of response to rituximab, OR 6.8 (95% CI 2.0-23.0, P = 0.002). Secondary ITP also remained a strong predictor of response to rituximab, OR 5.6 (95% CI 1.1-28.6, P = 0.04). Although 87.5% of patients who responded to steroids responded to rituximab, 48% with a negative response to steroids did respond to rituximab.In the NACIR, response to steroids and presence of secondary ITP were strong correlates of response to rituximab, a finding not previously reported in children or adults.

Abstract

MRI imaging of hepatic iron overload can be achieved by estimating T(2) values using multiple-echo sequences. The purpose of this work is to develop and clinically evaluate a weighted least squares algorithm based on T(2) Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) technique for volumetric estimation of hepatic T(2) in the setting of iron overload. The weighted least squares T(2) IDEAL technique improves T(2) estimation by automatically decreasing the impact of later, noise-dominated echoes. The technique was evaluated in 37 patients with iron overload. Each patient underwent (i) a standard 2D multiple-echo gradient echo sequence for T(2) assessment with nonlinear exponential fitting, and (ii) a 3D T(2) IDEAL technique, with and without a weighted least squares fit. Regression and Bland-Altman analysis demonstrated strong correlation between conventional 2D and T(2) IDEAL estimation. In cases of severe iron overload, T(2) IDEAL without weighted least squares reconstruction resulted in a relative overestimation of T(2) compared with weighted least squares.

Abstract

Disseminated intravascular coagulation (DIC) due to red cell hemolysis has been previously attributed to transfusion-related hemolytic reactions, but not to autoimmune hemolytic anemia. We report a case of DIC in a child with complement-fixing IgM-mediated cold-agglutinin autoimmune hemolysis, which resulted in arterial thrombosis and gangrene of the upper and lower extremities.

Abstract

We report four cases of diffuse infantile hepatic hemangioma, a rare but potentially life-threatening subset of hepatic hemangiomas. All patients demonstrated distinctive dome-shaped red-purple cutaneous hemangiomas. Two patients responded to steroids and propranolol (one in combination with vincristine), and two responded to steroids and vincristine. After a systematic literature review, we identified 26 previously reported cases of diffuse infantile hepatic hemangioma. Diffuse infantile hepatic hemangioma had a mortality rate of 17% and a >70% incidence of hypothyroidism, often severe (n = 30). More than one-third of patients developed heart failure (high output in half the cases). Based on our experience, early aggressive medical management, as well as thyroid replacement when indicated, should be initiated early in the course of diffuse infantile hepatic hemangioma pending evaluation for liver transplant.

Abstract

Pediatric immune thrombocytopenia (ITP) is usually self-limited. However, approximately 20% of children develop chronic ITP, which can be associated with significant morbidity because of long-term immunosuppression and splenectomy in refractory cases. To explore the molecular mechanism of chronic ITP compared with acute ITP, we studied 63 pediatric patients with ITP. Gene expression analysis of whole blood revealed distinct signatures for acute and chronic ITP. Oxidative stress-related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. Studies of normal persons demonstrated VNN1 expression in a variety of blood cells. Exposure of blood mononuclear cells to oxidative stress inducers elicited dramatic up-regulation of VNN1 and down-regulation of PPAR?, indicating a role for VNN1 as a peripheral blood oxidative stress sensor. Assessment of redox state by tandem mass spectrometry demonstrated statistically significant lower glutathione ratios in patients with ITP versus healthy controls; lower glutathione ratios were also seen in untreated patients with ITP compared with recently treated patients. Our work demonstrates distinct patterns of gene expression in acute and chronic ITP and implicates oxidative stress pathways in the pathogenesis of chronic pediatric ITP.

Abstract

Regular, chronic red cell transfusions (CTX) have been shown to be effective prophylaxis against stroke in sickle cell disease (SCD) in those at risk. Because serial brain imaging is not routinely performed, little is known about the impact of CTX on silent infarcts (SI) and cerebral vascular pathology. Thus, we retrospectively evaluated the magnetic resonance imaging reports of a cohort of SCD patients who were prescribed CTX for either primary or secondary stroke prophylaxis. Seventeen patients with Hb SS were included (mean age 15 years, mean follow-up 4.3 years). Eight patients were on CTX for primary prophylaxis. New SI occurred in 17.6% of patients corresponding to an SI rate of 5.42 per 100 patient-years. Vasculopathy of the cerebral arteries was present in 65% of patients and progressed in 63% of these patients. Those who developed progressive vasculopathy were on CTX for an average of 8 years before lesions progressed. Patients on CTX for secondary prophylaxis had more SIs and evidence of progressive vascular disease than patients on CTX for primary prophylaxis. We conclude that adherence to CTX does not necessarily prevent SI or halt cerebral vasculopathy progression, especially in those with a history of overt stroke.

Abstract

People with bleeding disorders may develop severe arthritis due to joint hemorrhages. Exercise is recommended for people with bleeding disorders, but guidelines are vague and few studies document efficacy. In this study, 65% of people with bleeding disorders surveyed reported participating in minimal exercise, and 50% indicated a fear of exercise-induced bleeding, pain, or physical impairment.The purpose of this study was to examine the feasibility, safety, and efficacy of a professionally designed, individualized, supervised exercise program for people with bleeding disorders.A single-group, pretest-posttest clinical design was used.Thirty-three patients (3 female, 30 male; 7-57 years of age) with mild to severe bleeding disorders were enrolled in the study. Twelve patients had co-existing illnesses, including HIV/AIDS, hepatitis, diabetes, fibromyalgia, neurofibromatosis, osteopenia, osteogenesis imperfecta, or cancer. Pre- and post-program measures included upper- and lower-extremity strength (force-generating capacity), joint range of motion, joint and extremity circumference, and distance walked in 6 minutes. Each patient was prescribed a 6-week, twice-weekly, individualized, supervised exercise program. Twenty participants (61%) completed the program.Pre- and post-program data were analyzed by paired t tests for all participants who completed the program. No exercise-induced injuries, pain, edema, or bleeding episodes were reported. Significant improvements occurred in joint motion, strength, and distance walked in 6 minutes, with no change in joint circumference. The greatest gains were among the individuals with the most severe joint damage and coexisting illness.Limitations included a small sample size with concomitant disease, which is common to the population, and a nonblinded examiner.A professionally designed and supervised, individualized exercise program is feasible, safe, and beneficial for people with bleeding disorders, even in the presence of concomitant disease. A longitudinal study with a larger sample size, a blinded examiner, and a control group is needed to confirm the results.

Abstract

Subject retention and adherence are essential to maintain the power and validity of the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). We designed a study to assess adherence with study medication administration and study visits and to evaluate socioeconomic factors (SES) that may influence these measurements of adherence. These data are important for assessing impact of adherence on BABY HUG trial outcome and defining impact of SES on adherence.Each subject's median study medication (MedAd) and mean visit adherence (VAd) were evaluated. We examined associations of adherence with SES of participating families.MedAd data were available on 153 of the 191 subjects who started randomized study medication. MedAd was 101.7% of volume prescribed, with 88.9% of subjects taking at least 80% of doses. VAd data were available on 185 of the 191 subjects who started randomized study medication. VAd was 97.3%, with 82.2% of subjects having no missed visits. During dose titration, subjects had on average 12.9% higher medication adherence than subjects who were on a stable dose and had less frequent study visits. MedAd and VAd were not significantly associated with SES.Subjects in the BABY HUG trial have had excellent adherence. SES was not associated with adherence, suggesting that SES should not be used as a criterion for enrolment in clinical trials. Additional efforts are needed to maintain medication adherence, particularly when the interval between scheduled visits increases. (ClinicalTrials.gov number, NCT00006400).

Abstract

We identified four patients who presented with BCR-ABL1 negative myeloproliferative neoplasms and cytogenetically visible abnormalities of chromosome band 5q31-35. Fluorescence in situ hybridization indicated that the platelet-derived growth factor receptor beta gene (PDGFRB) was disrupted in all four cases and 5' rapid amplification of cDNA ends identified in-frame mRNA fusions between PDGFRB and WDR48 (3p21), GOLGA4 (3p21) and BIN2 (12q13). Strikingly, all three genes encode proteins involving intracellular trafficking. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of t(3;5) myeloid colonies and produced clinically significant responses in all patients. We conclude that PDGFRB fuses to diverse partner genes in atypical myeloproliferative neoplasms (MPNs). Although very rare, identification of these fusions is critical for proper management of affected individuals.

Abstract

Central venous access devices (CVAD) have been effectively used in the care of haemophilia patients. This is particularly true in children, who often have difficult venous access. CVAD complications (infection and thrombosis), risk factors, and complication rates, have been well-documented. However, effective interventions which decrease complication rates have not been identified. In this study, we review our experience with the use of monthly recombinant tissue plasminogen activator (rtPA) administration in haemophilia patients with fully implanted CVADs. Data on 19 haemophilia patients with 24 CVADs were available for analysis, with a total of 24 520 CVAD days. An infection rate of 0.04 infections per 1000 CVAD days and a thrombosis rate of 0.04 thrombi per 1000 CVAD days was observed. The observed infectious complication rate is at least one logarithm lower than many published CVAD infection rates in haemophilia patients who have not received rtPA administration. No bleeding complications were noted. Monthly rtPA is safe and appears to be effective in decreasing CVAD infection rates. Larger, randomized controlled studies are indicated to validate this finding.

Abstract

Neonatal thrombocytopenia or neutropenia may result from passive transfusion of maternally derived antibodies. Antibodies against platelet antigens are commonly associated with neonatal alloimmune thrombocytopenia (NAIT), and anti-neutrophil antibodies are frequently identified in alloimmune neonatal neutropenia (ANN). Combined alloimmune cytopenias in the newborn are rarely reported; even fewer reports document human leukocyte antigen (HLA) antibodies as a potential cause of neonatal thrombocytopenia or neutropenia. We describe neutropenia and thrombocytopenia in a newborn associated with markedly elevated maternal HLA antibodies in the absence of anti-neutrophil or anti-platelet antibodies to highlight consideration of HLA antibodies in the pathogenesis of ANN and NAIT.

Abstract

Idiopathic neutropenia (IN) in children is characterized by decreased neutrophil counts (<1500/microl), can be acute or chronic (greater than 6 months duration). The pathophysiology is not well understood; therefore, potential mechanisms of pediatric IN were investigated. An increase in Fas transcripts in neutrophils of IN patients compared to age-matched healthy control (HC) neutrophils was observed (p<0.005). Increased expression of Fas protein was found in IN neutrophils, while Fas surface expression on other immune cells was similar. Plasma from acute IN patients had higher protein levels of soluble FasL than chronic IN patients. When HC neutrophils were incubated in plasma from IN patients, greater rates of apoptosis were observed. Biochemical studies suggest the apoptotic factor(s) in plasma is heat-sensitive, non-IgG, and 12-50 kD protein. Addition of anti-sFasL blocking antibodies to patient plasma caused a statistically significant decrease in neutrophil apoptosis. These studies show that the Fas/FasL pathway could be associated with neutrophil apoptosis in childhood IN.

Abstract

Patients with multi-system Langerhans cell histiocytosis (LCH) who progress on frontline therapy have a dismal outcome. Responses to cladribine have been reported in relapsed LCH, but there are no well defined salvage regimens for LCH is refractory to therapy. The next generation deoxyadenosine analog, clofarabine, has demonstrated activity in patients with leukemia that is refractory to salvage regimens, including other nucleotide congeners; however, no experience exist on the use of clofarabine in LCH. In this report we describe significant single agent activity of clofarabine in disseminated LCH refractory to salvage regimens, including cladribine.

Abstract

Despite the efforts of many hospitals, system failures can result in medication errors that may be life threatening. During 2006 and 2007, nine neonates received potentially fatal doses of heparin. This paper will review contributing factors to the heparin medication errors and ways to minimize the risk of heparin overdose.

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome which can be an inherited congenital disorder or can develop secondary to malignancy, infection, or autoimmune disease. Secondary HLH due to malignancy occurs most commonly with T or NK-cell lymphoid neoplasms. HLH with B-cell malignancies is less common and HLH has rarely been described in association with precursor B-cell acute lymphoblastic leukemia (B-ALL). We report three cases of HLH associated with B-ALL and review 17 cases of ALL-associated HLH previously reported in the literature.

Abstract

A global expression profile of peripheral blood from patients with immune thrombocytopenic purpura (ITP) was performed that identified an ITP-specific signature, which also included interferon (IFN)-induced genes. Several genes correlated with ITP have been shown to be associated with expression signatures in systemic lupus erythematosis and rheumatoid arthritis, indicating an overlap with other autoimmune disorders. Pathway analysis demonstrated that IFN signalling, death receptor and protein ubiquitination pathways were associated with ITP. These results provide the first glimpse of the genes and pathways consistently aberrant in ITP, identifying new targets for investigations of pathogenesis and treatment of ITP.

Abstract

Anemia is a common finding in post-liver transplant patients. Causes for the anemia include nutritional deficiencies, red cell aplasia as well as immune-mediated hemolysis. One of the immunologic causes of hemolytic anemia is drug-induced hemolysis. Tacrolimus is a common immunosuppressant used in post-liver transplant patients to prevent graft rejection. There have been reports of tacrolimus-associated hemolytic anemia secondary to hemolytic uremic syndrome as well as autoimmune hemolysis. There are also case-reports of severe hemolytic anemia related to cold agglutinin production in post-liver transplant patients. We described in this paper three cases of severe cold agglutinin hemolytic anemia in three pediatric liver transplant patients. Steroid therapy, plasmapheresis and withdrawal of tacrolimus led to resolution of the severe hemolytic process in each case. Whether the immune-mediated hemolysis is related to tacrolimus is not clear and needs to be characterized further.

Abstract

The most widely used drug for iron chelation is deferoxamine (DFO) mesylate. While effective in promoting iron excretion, it requires prolonged daily infusions, often resulting in poor compliance. A clinical trial was conducted using starch-conjugated DFO (S-DFO; 40SD02), a high-molecular-weight iron chelator possessing prolonged vascular retention. Single doses of S-DFO were infused intravenously into groups of four transfusion-dependent patients with beta-thalassaemia at doses of 150, 300, 600 and 900 mg/kg. Urinary iron excretion and various pharmacologic parameters were evaluated for 1 week and safety for 3 weeks. No drug-related effects were observed on clinical chemistries, haematological and coagulation parameters, urinalyses, vital signs or electrocardiograms. Drug-related adverse events were limited to four urticarial reactions, none requiring termination of the infusion. The drug stimulated clinically significant urinary iron excretion, with the highest dose (900 mg/kg) inducing excretion of 1.31 mg of iron/kg (range 0.79-1.90 mg/kg) over 1 week, with residual iron-binding capacity present in the plasma for over 6 d. In summary, treatment with S-DFO, administered weekly, has the potential to achieve iron balance in the poorly compliant patient.

Abstract

Iron chelation therapy (ICT) with deferoxamine (DFO), the current standard for the treatment of iron overload in patients with transfusion-dependent disorders such as beta-thalassemia, requires regular subcutaneous or intravenous infusions. This can lead to reduced quality of life and poor adherence, resulting in increased morbidity and mortality in iron-overloaded patients with beta-thalassemia. Deferasirox is an orally administered iron chelator that has been approved for use in the United States, Switzerland, and other countries.This analysis was conducted to compare patient-reported outcomes (PROs) during receipt of DFO infusions or once-daily oral therapy with deferasirox (ICL670).PROs were prospectively evaluated as part of a randomized, Phase III study comparing the efficacy and safety profile of DFO 20 to 60 mg/kg per day with those of deferasirox 5 to 30 mg/kg per day in patients (age > or =2 years) with beta-thalassemia who were receiving regular transfusions and had a liver iron concentration of > or =2 mg/g dry weight. PRO questionnaires were completed by patients or a parent or legal guardian at baseline, week 4, week 24, and end of study (EOS). Patients assessed their level of satisfaction with study treatment (very satisfied, satisfied, neutral, dissatisfied, or very dissatisfied) and rated its convenience (very convenient, convenient, neutral, inconvenient, or very inconvenient). Time lost from normal activities due to ICT in the previous 4 weeks was recorded using a single global assessment. At week 4, patients who had previous experience with DFO were asked to indicate their preference for treatment (ICT received before the study, ICT received during the study, no preference, or no response) and the reason for that preference. At EOS, all patients were asked if they would be willing to continue using the ICT they had received during the study. All study analyses were performed in all patients who received at least 1 dose of study medication.Five hundred eighty-six patients (304 females, 282 males; age range, 2-53 years) received treatment with DFO (n = 290) or deferasirox (n = 296). Significantly more patients treated with deferasirox reported being very satisfied or satisfied with treatment compared with those treated with DFO (week 4: 92.0% vs 50.4%, respectively; week 24: 89.6% vs 44.0%; EOS: 85.1% vs 38.7%; all, P < 0.001). At the same time points, the majority of those treated with deferasirox reported that treatment was very convenient or convenient compared with those treated with DFO (95.5% vs 21.3%, 91.7% vs 17.4%, and 92.7% vs 11.3%, respectively; all, P < 0.001). Among patients who had previously taken DFO and were randomized to receive deferasirox during the study, 96.9% reported a preference for deferasirox over DFO. At EOS, the proportion of patients indicating a willingness to continue study therapy was significantly greater in those receiving deferasirox than in those receiving DFO (85.8% vs 13.8%; P < 0.001).In this study, patient-reported satisfaction and convenience were significantly higher for the once-daily, oral ICT deferasirox than for DFO infusions. Among patients who had received DFO before the study, the majority indicated a preference for deferasirox over DFO. Most patients receiving deferasirox indicated that they would be willing to continue taking it. These results suggest that deferasirox had a positive impact on patients' daily lives.

Abstract

Our objective was to describe the efficacy of darbepoetin alfa and ferric gluconate complex in the treatment of the anemia associated with recessive dystrophic epidermolysis bullosa. To accomplish this aim, we retrospectively reviewed a series of patients with this disease treated in a single institution with darbepoetin alfa and parenteral iron for anemia. Four patients with recessive dystrophic epidermolysis bullosa were treated for a mean length of treatment of 14.5 months (4-18 months). Three patients received parenteral iron in the form of ferric gluconate complex and one received iron dextran. The mean pretreatment hemoglobin was 6.8 g/dL (4.9-9.6 g/dL). All four had improvements in their hemoglobin levels and energy levels with a mean increase in hemoglobin level of 2.8 g/dL (p = 0.003). We found darbepoetin alfa and ferric gluconate complex to be effective in the treatment of anemia associated with recessive dystrophic epidermolysis bullosa and to have distinct advantages over previously described formulations, and we concluded that they should be considered in the supportive care of this disease. We recommend the development of a standardized protocol for the evaluation and management of recessive dystrophic epidermolysis bullosa-associated anemia.

Abstract

To search for novel mechanisms that contribute to the pathophysiology of idiopathic thrombocytopenic purpura (ITP), we determined the whole blood gene expression profile in five ITP patients and five control samples. Using DNA microarrays that contained 24,473 unique putative genes, we found 176 cDNAs that were strongly correlated with ITP. These included a cluster of interferon-regulated genes and TLR7, as well many less-well characterized genes which are candidates for further study. We believe this approach is likely to yield new insights into our understanding of the molecular pathophysiology of ITP.

Application of a geographic information system to explore associations between air pollution and micronucleus frequencies in African American children and adultsENVIRONMENTAL AND MOLECULAR MUTAGENESISHuen, K., Gunn, L., Duramad, P., Jeng, M., Scalf, R., Holland, N.2006; 47 (4): 236-246

Abstract

Exposure to air pollution has been associated with adverse respiratory and cardiovascular health outcomes in both children and adults. In this study, we used geographic information systems (GISs) to explore possible associations between chromosomal damage in 65 African American children and their mothers from Oakland, California, and both proximity to traffic and regional ozone levels. Study participants were interviewed at the Healthy Child Clinic of Children's Hospital, Oakland, and their blood and buccal cells were collected for assessment of chromosomal damage by the micronucleus (MN) assay. Regional ozone levels, which decreased from April to November with a secondary peak in late summer, were highly correlated with season by month (r=-0.84, P=0.02) and strongly associated with MN frequency (frequency ratio (FR): 3.37, 95% confidence interval (CI): 1.30-8.72) in both cell types of children and adults. Additionally, MN frequencies were modestly associated with individual measures of traffic density in children (FR=2.45, 95% CI=0.86-7.10), but not in adults; this suggests a greater vulnerability to traffic-related air pollution in children. Smoking in the household also increased MN frequency in the lymphocytes of children (FR: 1.13, 95%CI: 1.01-1.24) and adults (FR: 1.06, 95%CI: 0.99-1.13), whereas vitamin use in adults decreased MN frequency in both lymphocytes and buccal cells (FR: 0.17, 95%CI: 0.02-1.31; FR: 0.18, 95%CI: 0.03-1.18, respectively). Our data indicate that GIS-generated measures of traffic density for individual households augment regional ozone monitoring data used to assess effects of air pollution. This approach helped to demonstrate elevated cytogenetic damage in exposed minority children.

Abstract

Immunosuppressive therapy (IS) is effective in the treatment of patients with acquired severe aplastic anemia (SAA). An enhanced myeloid response and decreased infection risk may be possible with the addition of a hematopoietic cytokine. Published data on the combination of cytokines and IS in patients with SAA are limited. The addition of G-CSF to IS shortens the time to neutrophil count recovery, but may not improve overall survival. Because GM-CSF acts differently than G-CSF, its use in combination with IS may be different.A retrospective chart review was performed on patients diagnosed with SAA and treated with IS and GM-CSF at St. Jude Children's Research Hospital. Hematologic recovery, prognostic factors, and infection data were collected.Eighteen patients were included in this study. The median age at diagnosis was 7.2 years (range 1.8-17.0). Ten patients (56%) had a complete response, four (22%) a partial response, and four (22%) no response. Median time to erythrocyte and platelet transfusion independence were 90 (18,243) and 64 days (18-243), and to discontinuation of treatment 287 days (90-730). Median time to partial (ANC > 500) and full (ANC > 1,500) neutrophil recovery were 41 and 51 days, respectively. Seventeen documented discrete infections occurred in six patients over 36 patient years.GM-CSF, in addition to IS, may shorten time to neutrophil count recovery, may be beneficial in decreasing infection rates, and may improve platelet response in patients with SAA. However, consistent with studies utilizing G-CSF, GM-CSF probably does not affect overall response rate. To fully answer whether or not cytokine therapy is of added value to IS in pediatric patients, a multi-institutional randomized trial is needed.

Abstract

Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

Abstract

Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.

Abstract

The objective was to study the effects of chronic transfusion therapy (CTX) on the prevention of new episodes of acute chest syndrome (ACS) in children with sickle cell disease (SCD) and recurrent or unusually severe ACS. A retrospective chart review was performed of patients given CTX for recurrent or severe ACS. Frequency, median severity score, and median hospital stay for ACS episodes were determined. Differences in these values before and during CTX were analyzed. Twenty-seven patients were identified. Before treatment, the ACS incidence was 1.3 episodes per patient-year; during treatment, it decreased to 0.1 episodes per patient-year (P < 0.0001). The median severity score for ACS episodes was 0.8 (range 0-5) before CTX and 0.5 (0-3) during CTX (P = 0.84). The median hospital stay was 5 days (range 3-15 days) before CTX and 3 days (2-7 days) during CTX (P = 0.38). CTX significantly reduces the incidence of ACS events among patients with a history of recurrent or severe episodes but does not significantly decrease their severity. The effectiveness of CTX should be prospectively compared with that of hydroxyurea and stem cell transplantation.

Abstract

An increasing number of Southeast Asian immigrants have come to North America. Physicians who care for this population should be aware of the high prevalence of hematologic disorders and develop an approach to their diagnosis and management. Malaria and the hematologic sequelae, glucose-6-phophate dehydrogenase deficiency, the thalassemia syndromes, Southeast Asian ovalocytosis, visceral leishmaniasis, HIV infection, and iron-deficiency anemia, all of which may pertain to these patients, are reviewed in this article.

Abstract

Moderate aplastic anemia (MAA) in children is a rare, idiopathic condition of bone marrow insufficiency that can resolve spontaneously, persist for months or years, or progress to severe aplastic anemia (SAA). We evaluated the rate of progression to SAA.We reviewed the records of 136 children referred for evaluation of bone marrow failure from 1978 to 2002 at St. Jude Children's Research Hospital. MAA was defined by a hypocellular bone marrow (<50%) and 2 or 3 cytopenias (absolute neutrophil count <1,500/mm(3), absolute reticulocyte count <40,000/mm(3), platelet count <100,000/mm(3)) lasting at least 6 weeks.Twenty-four patients met the criteria for MAA. At a median follow-up of 66 months (range, 10-293), 16 patients (67%) progressed to SAA, 5 (21%) had persistent MAA, and 3 (12%) had complete resolution of MAA. No risk factors for progression could be identified.When childhood MAA is treated with supportive care alone, 2/3 of patients progress to SAA.

Abstract

Both hyper-IgE syndrome and food allergies can result in the early onset of skin rash, eosinophilia, and markedly elevated serum IgE. Occasionally, it can be difficult to distinguish the 2 disorders. Most patients with hyper-IgE syndrome do not have food allergy.To describe a child with cow's milk allergy associated with hyper-IgE syndrome manifesting as failure to thrive (FTT).Epicutaneous skin prick test to cow's milk, CAP radioallergosorbent test, atopy patch tests, and double-blind, placebo-controlled milk challenge (DBPCMC) were performed.During initial presentation at 3 weeks of age, the circulating eosinophil count increased from 13,800/mm3 to 44,254/mm3 within 2 weeks while taking cephalexin. Despite treatment, he had worsening rash and FTT at 10 weeks of age with an IgE level of 8,454 U/mL. After changing from an infant milk formula with whey protein to an amino acid-based formula in combination with oral antibiotic treatment, his rash and growth velocity improved markedly within 2 months. IgE decreased to 2,747 U/mL. He remained clinically well for 12 months. He subsequently developed additional food and inhalant allergies with an increase in IgE to 12,150 U/mL. Cow's milk allergy was confirmed by epicutaneous skin prick test, atopy patch test, and DBPCMC.Traditional prophylactic antistaphylococcal antibiotics, in combination with Neocate formula, were effective in treating the early skin manifestations of hyper-IgE syndrome and FTT in this infant. Cow's milk protein allergy should be considered in patients with hyper-IgE syndrome and FTT.

Abstract

Sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai-Dorfman disease (RDD), is a histiocytic disorder that usually presents with painless massive cervical lymphadenopathy. The course is usually self-limited, but treatment may be required in cases with compression of vital organs. Patients may present with extranodal involvement only, and in these cases the clinical and histologic diagnosis may be difficult. The authors describe three patients with RDD who had exclusive extranodal disease in the head and neck area, in whom the clinical presentation mimicked other more common conditions.

Abstract

Red blood cells containing hemoglobin S are less deformable than normal erythrocytes and have a major effect on the viscoelasticity of blood. This alteration in rheology increases the impedance to flow, leading to an increase in RBC aggregation and reduction in oxygen saturation, which induces further sickling and occlusions in the microcirculation. Patients with sickle cell disease (SCD) can experience severe complications, such as acute pain and stroke. Automated red blood cell exchange transfusion, or erythrocytapheresis, is used with homozygous SCD (Hb SS) to replace sickled cells with normal cells, thereby decreasing the percentage of sickle hemoglobin (%Hb S) and maintaining a net balance in iron accumulation. These patients received monthly erythrocytapheresis with a goal to maintain a pre-pheresis %Hb S at less than 30%. In this study, viscoelastic parameters were used to quantify the effectiveness of this therapy for six patients undergoing chronic erythrocytapheresis. Whole blood viscosity, elasticity and relaxation time at oscillatory strains of 0.2, 1 and 5, and hematocrit and %Hb S were measured prior to erythrocytapheresis and 15 minutes after completion and compared with normal reference values at the patient's hematocrit. This study confirms the beneficial effects on viscosity, elasticity, and relaxation time of erythrocytapheresis.

Abstract

Red blood cells containing hemoglobin S are less deformable than normal erythrocytes and have a major effect on the viscoelasticity of blood. This alteration in rheology increases the impedance to flow, leading to an increase in RBC aggregation and reduction in oxygen saturation, which induces further sickling and occlusions in the microcirculation. Patients with sickle cell disease (SCD) can experience severe complications, such as acute pain and stroke. Automated red blood cell exchange transfusion, or erythrocytapheresis, is used in homozygous SCD (Hb SS) to replace sickled cells with normal cells, thereby decreasing the percentage of sickle hemoglobin (%Hb S) and maintaining a net balance in iron accumulation. These patients received monthly erythrocytapheresis with a goal to maintain a pre-pheresis %Hb S at less than 30%. In this study, viscoelastic parameters were used to quantify the effectiveness of this therapy for six patients undergoing chronic erythrocytapheresis. Whole blood viscosity, elasticity and relaxation time at oscillatory strains of 0.2, 1 and 5, and hematocrit and %Hb S were measured prior to erythrocytapheresis and 15 minutes after completion and compared with normal reference values at the patient's hematocrit. This study confirms the beneficial effects on viscosity, elasticity, and relaxation time of erythrocytapheresis.

Abstract

Three polymorphic gene mutations in the human hemochromatosis (HFE) gene (C282Y, H63D, S65C) are associated with non-transfusion-related iron overload in Caucasians. More recently, these mutations have also been identified in African-Americans. However, the prevalence of HFE gene mutations in African-Americans with sickle cell disease (SCD) has not been described. The presence of these mutations in this population is particularly important, because patients with SCD may be placed on chronic red cell transfusion therapy and are thus at further risk for iron overload. Thus, we attempted to establish the gene mutation prevalence in African-Americans with SCD, to compare this frequency with published gene frequencies in African-Americans, and to evaluate their significance with regard to transfusion-related iron overload. Eighty-nine African-American patients with SCD, all of whom were receiving chronic red cell transfusion therapy, were screened by DNA analysis for the three HFE gene mutations. Two patients were heterozygous for the C282Y HFE mutation (2.3%), six were heterozygous for the H63D mutation (6.8%), none carried the S65C mutation (0.0%), and no homozygous or compound heterozygous subjects were identified. The prevalence of C282Y and H63D in the SCD population was similar to that observed in the general African-American population. In addition, there was no increased mutation prevalence when comparing those SCD patients on chronic transfusion therapy who had ferritin levels greater than 2,500 ng/mL and those less than 2,500 ng/mL. This study represents the first identification of the known HFE gene mutations by DNA analysis in the SCD population. We conclude that the presence of recognized HFE coding region mutations do not seem to have an impact on the degree of iron overload in patients with SCD receiving chronic transfusion therapy.

Abstract

Budd-Chiari syndrome (BCS) is uncommon in the children. The cause of BCS comprises several diseases leading to thrombophilia. Activated protein C resistance as a result of a single gene mutation in factor V, the so called factor V Leiden (FVL), is the most common cause of thrombophilia.We report a simultaneous occurrence of BCS in identical twin sisters of 13 years of age with heterozygous FVL mutation.One sister presented with acute BCS leading to fulminant hepatic failure. She underwent liver transplantation with subsequent normalization of activated protein C resistance. The other twin sister, who was diagnosed with extensive thromboses of the inferior vena cava, portal vein, and hepatic veins, was successfully managed by aggressive chemical and mechanical thrombolysis followed by therapeutic anticoagulation. Genomic DNA studies confirmed heterozygosity of FVL mutation in the sisters' father and older brother.The exact cause of the BCS in children should be thoroughly and rapidly investigated, and, if necessary, immediate family members should also be tested for genetic defects in factor V or concomitant thrombophilia.

Abstract

Hepatic sequestration is an uncommon complication in patients with homozygous sickle cell disease. Although transfusion therapy has been effective for the acute condition, no definitive treatment of chronic hepatic sequestration has been identified. We describe a 17-year-old male patient with hemoglobin SS and chronic hepatic sequestration who was treated with long-term (60 months) hydroxyurea. After 36 months of HU therapy, the patient had both an excellent hematologic response and a resolution of hepatic sequestration, as evidenced by disappearance of clinical hepatomegaly, normalization of liver volume on serial computed tomography scans, as well as decreased sinusoidal dilatation and congestion and red blood cell sickling on liver biopsy. The findings in this case suggest that hydroxyurea may benefit patients who have unusual complications of sickle cell disease, such as chronic erythrocyte sickling in the liver.

Abstract

A 13-year-old boy and a 16-year-old girl both presented with headaches and nausea after they were diagnosed with severe acquired aplastic anemia. Both patients had symptoms and signs consistent with the clinical syndrome of pseudotumor cerebri including headaches, nausea, papilledema, and elevated intracranial pressure. Both patients were treated with therapeutic lumbar puncture and acetazolamide, which relieved their symptoms. Acetazolamide dosage was given while the patients underwent an immunosuppressive regimen. We hypothesize that the pseudotumor cerebri in these two pediatric patients was the result of an increased production of cerebrospinal fluid in response to anemia and that the removal of fluid and treatment with acetazolamide appear to be helpful in such cases.

Abstract

Langerhans cell histiocytosis (LCH) is a disorder characterized by proliferation of activated Langerhans cells. Immune dysregulation is believed to be part of the pathogenesis. Although current therapies are very effective at inducing remission, multiple recurrences and long-term sequelae are common for patients with low-risk disease, and a significant proportion of young patients die of their disease. More effective therapies based on the pathogenesis of LCH are needed. We investigated the use of 2-chloro-deoxyadenosine (2-CdA), a purine analogue with an antiproliferative effect on histiocytes and lymphocytes, in patients with recurrent or high-risk LCH. Six patients with recurrent LCH received 2-CdA (5-7 mg/m(2)/day for 5 days, repeated every 21-28 days). All patients achieved remission. With a median follow-up of 15 months (range, 3-25 months), 5 patients remain in remission. A patient with multisystem disease who recurred after 13 months, achieved a second remission with 2-CdA. Hematologic toxicity was minimal, and no infectious complications were documented. 2-CdA is among the most effective drugs for the treatment of LCH, and this is probably due to both its anti-proliferative and immunomodulatory effects. 2-CdA needs to be considered for the treatment of recurrent LCH. However, its incorporation into front-line treatment of patients with multi-system LCH needs further study.

Abstract

A review of patients with sickle cell disease (SCD) and central venous catheters (CVCs) was performed to evaluate the frequency of catheter complications (infections, thrombotic events, and premature CVC removal. Fifteen evaluable patients were identified during our review of a 7.5-year period. The median age was 18 years (range, 1.5-30 years); 14 were African American, and 1 was Latino; 5 were male, and 10 were female. Forty-one CVCs were placed (36 Mediport and 5 Broviac catheters) for a total of 12,120 CVC days. We observed a median of 2 CVCs per patient (range, 1-8 CVCs per patient) with 67 discrete episodes of CVC-associated infection (range, 0-18 per patient) involving 10 patients. The rate of CVC-associated infection for patients with SCD at our institution was 5.5 infections per 1,000 CVC days; this rate was significantly higher than the rate of CVC-associated infection in our patients with cancer (P < 0.001). We also determined that the rate of CVC-associated thrombosis was 0.99 events per 1,000 CVC days and involved 33% of the patients with SCD; the rate of premature CVC removal was 3.15 per 1,000 CVC days, and 78% of CVCs were removed prematurely. We conclude that patients with SCD are at high risk for CVC-related complications, and improved care and close monitoring of CVCs should be encouraged to decrease morbidity in these chronically ill patients.

Abstract

A boy with acute lymphoblastic leukemia (ALL) experienced life-threatening vincristine neurotoxicity while simultaneously exposed to itraconazole. Five pediatric and six adult cases of itraconazole-enhanced vincristine toxicity have been reported, all with ALL. Upon cessation of the itraconazole, the patient's symptoms resolved, which is similar to the outcome of the previously reported cases: 10 of 11 patients had complete resolution of symptoms.

Abstract

Benzene is an established human carcinogen, producing leukemia, hematotoxicity and perhaps lymphoma. Its carcinogenicity is most likely dependent upon its conversion to phenol and hydroquinone, the latter being oxidized to the highly toxic 1,4-benzoquinone in the bone marrow. Exposure of human lymphocytes and cell lines to hydroquinone has previously been shown to cause various forms of genetic damage, including aneusomy and the loss and gain of chromosomes. However, the target cells for leukemogenesis are the pluripotent stem cells or early progenitor cells which carry the CD34 antigen (CD34(+) cells). In this study, human cord blood, which is particularly rich in CD34(+) cells, was exposed to hydroquinone for 72 h in a medium that favored CD34(+) cell survival and growth. CD34(+) and CD34(-) cells were then isolated. Fluorescence in situ hybridization was employed to determine the level of aneusomy of chromosomes 7 and 8 in both cell types. CD34(+) cells were generally more susceptible to aneusomy induction by hydroquinone than CD34(-) cells. Increased trisomy and monosomy of chromosomes 7 and 8 were observed in CD34(+) cells (P(trend) < 0.001), whereas in CD34(-) cells only an increased level of monosomy 7 was detected (P(trend) = 0.002). Particularly striking effects of hydroquinone were observed in CD34(+) cells on monosomy 7 and trisomy 8, two common clonal aberrations found in myeloid leukemias, suggesting that these aneusomies produced by hydroquinone in CD34(+) cells play a role in benzene-induced leukemogenesis.